Major changes in this edition include the substitution of probabilistic arguments for combinatorial artifices, and the addition of new sections on branching.

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These cognitive processes are often linked to alertness. Sleepiness and sedating medications can impair attention and working memory function.

These cognitive processes involve the frontal and parietal lobes in the brain. Working memory also involves the basal ganglia and dorsolateral prefrontal cortex, regions affected in PD. Executive function includes the ability to plan, organize, initiate, and regulate goal directed behavior. These activities may include multitasking, solving problems, starting new tasks, and switching tasks.

Executive function involves the prefrontal cortex of the brain and the dopamine system, which are affected in PD. Executive dysfunction is one of the most common cognitive changes reported in PD. In general, the concept of memory invokes learning and remembering information. Memory, however, can be classified into different processes and types. For instance, there is immediate seconds-minutes , short-term minutes-days , and long-term memory days-years.

There also is memory for facts, concepts, or events called declarative memory and memory for how to do certain tasks like tie our shoes or ride a bicycle called procedural memory as well as working memory described earlier. In PD, people frequently recall information more readily when given cues or choices. Long-term memory function typically remains intact in PD. Language abilities include naming objects, generating words, comprehension, and verbal concepts. This can be an area of frustration for both the patient and caregiver because verbal communication is such an important part of human behavior.

These abilities tell us where things are around us in space, give us a spatial map of our environment, and involve our sense of direction. Visuospatial functions allow us to estimate distance and depth perception, use mental imagery, copy drawings, or construct objects or shapes. These abilities rely on the parietal lobe of the brain. There are several ways to assess cognition in the clinical or in the research setting. These evaluations include multiple tests to assess different cognitive domains.

Some of the tests require oral answers, while others use a pencil and paper. This evaluation may range from about 45 minutes to several hours. In some people with PD, the cognitive changes are mild. In others, however, cognitive deficits may become more severe and impact daily functioning. Attention and working memory, executive function, and visuospatial function are the most frequently affected cognitive domains in PD. They may or may not be noticeable to the person. They may or may not affect work or activities, depending on the demands of specific tasks and work situations.

Dementia refers to a syndrome in which patients have problems in more than one cognitive domain, and the cognitive problems significantly impair everyday life functioning. Besides PD, there are other important causes of cognitive dysfunction to keep in mind. Medical illnesses such as thyroid disease or vitamin B12deficiency can cause cognitive symptoms. Urinary tract infections or pneumonia can acutely cause confusion or hallucinations. In these settings, the cognitive symptoms are generally reversible after the infection or medical condition is treated.

However, among them, the memory tasks are the most suitable for PD diagnosis Muslimovic et al. As a potential important contribution to the diagnosis of PD cognitive deterioration, there is an increasing effort in the identification of biomarkers such as cerebrospinal fluid, and genetic and neuroimaging biomarkers. However, at present, both an unequivocal clinical definition and a clear pathophysiological knowledge of the cognitive symptoms in PD are still matters of debate.

In fact, whereas the motor impairment is considered to be mainly caused by the progressive degeneration of the dopaminergic nigrostriatal pathway, the etiopathology of the cognitive decline associated with PD is still unknown Dubois and Pillon ; Chaudhuri and Schapira Clinical studies based on functional imaging techniques Carbon and Marie suggest that cognitive symptoms might not only be partially dependent on the death of dopaminergic neurons in the substantia nigra, but also linked to the consecutive involvement of other brain regions, such as prefrontal cortex Owen , hippocampus Bruck et al.

These data are also supported by preclinical results showing that, in experimental parkinsonian models, the animals are impaired in behavioral tasks mainly mediated by brain areas other than the striatum, such as the hippocampus or the prefrontal cortex, as reported above.

Notably, it seems that cognitive deficits in PD patients emerge from tests sensitive to frontal lobe dysfunction i. Moreover, increasing evidence suggests that the cognitive decline reported in PD patients is not simply related to a mere dopaminergic deficit. Indeed neurodegeneration in PD, besides affecting dopaminergic neurons in the substantia nigra, also appears in the locus coeruleus, the main noradrenergic site Vazey and Aston-Jones , the raphe nuclei, location of serotoninergic neurons Fox et al. Thus, the fine balance among the dopamine, noradrenaline, serotonin, and acetylcholine brain systems is massively disrupted.

In line with a heterogeneous neurobiological substrate of the disease, whereas motor symptoms are successfully treated with dopamine replacement therapies, such as L-DOPA administration, cognitive symptoms are only partially responding to these drugs Kulisevsky et al. Noteworthy, it has long been debated whether dopamine replacement medications, while improving motor symptoms, have a deleterious Antonini and Cilia , beneficial Lange et al.

In this regard, it has been suggested that the positive or negative effects on cognitive ability could depend on the severity of the disease and the specific skill being tested. However, not only are there no available drugs able to revert both motor and nonmotor PD deficits, but also there is no specific suitable treatment for NMS with therapies commonly used in non-PD patients, without taking into consideration the coadministration of typical antiparkinsonian drugs to these patients. Thus, in order to identify specific treatments for NMS, it remains imperative to better understand, through clinical and preclinical studies, the neuropathology underlying these symptoms.

As the cognitive impairment in PD patients became a relevant issue, the preclinical research started developing new tools suitable for the study of these deficits. In particular, among the extended range of nonmotor, cognitive deficits appearing in PD patients mentioned above, several animal models have been recently validated for the study of spatial and discriminative memory, attention, and learning abilities related to the disease. MPTP can be systemically administered in mice, but must be locally injected into specific brain regions in rats.

This model is used to reproduce motor Gerlach and Riederer , as well as nonmotor, deficits Fox et al. However, the occurrence of Lewy body formations following the administration of MPTP has been observed but not later confirmed Fornai et al. Most important, it has been suggested that in MPTP-intoxicated animals, the dopaminergic fiber loss can spontaneously recover Beal , making this model difficult to use for longitudinal studies to assess progressive cognitive impairments.

The use of nonhuman primates in PD research has a long history. In the first experiments, macaques were submitted to unilateral intracarotidian injection Benazzouz et al.

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In these studies, the ability of MPTP to affect neurotransmitters other than dopamine has been shown and related to the concomitant loss of noradrenaline and serotonin found in the brain of PD patients Pifl et al. Animal models based on the use of nonhuman primates certainly represent a crucial tool for the study of human diseases in general and of cognition in particular, due to their motor and cognitive skills as well as their neuroanatomical complexity closely resembling those of humans.

However, economical and ethical considerations still limit the employment of monkeys in preclinical research. Due to its inability to cross the BBB, this neurotoxin needs to be injected directly into the target brain structure Gerlach and Riederer , where it binds receptor transporters and retrogradely kills the neurons by oxidative stress.

Because of the structure similarity, 6-OHDA is taken up by terminals of catecholaminergic neurons at the side of injection. Thus, to selectively affect dopamine cells and better mimic PD dopaminergic degeneration, the toxin can be administered together with inhibitors of noradrenaline and serotonin transporters e. The direct injection of the toxin into the SNpc or the MFB causes a fast and massive degeneration of dopaminergic cell bodies that therefore involves the nigrostriatal pathway according to an anterograde progression. Conversely, 6-OHDA injection into the striatum initially affects the dopaminergic terminals and thus damages the striatonigral pathway and the projecting structures according to a retrograde progression Tadaiesky et al.

Administration of 6-OHDA has been largely used to reproduce the hemiparkinsonian rodent model for the study of the motor symptoms of the disease. In this case, some changes to the injection protocol are strongly suggested. First, the toxin should be injected bilaterally into the brain, in order to avoid the possible compensatory effect of the unlesioned hemisphere on the lesioned one on the behavioral performance.

Notably, a bilateral symmetric dopamine depletion would prevent the confounding effect of an asymmetric motor output. Importantly, such modified protocol is not only more suitable for the study of cognitive NMS, but it also results in a model that resembles much more the parkinsonian condition. On the other hand, it is worth noting that this type of lesion neither mimics the progressive dopaminergic degeneration characterizing PD in patients nor is it accompanied by the formation of Lewy bodies normally found in PD brains. In this regard, many different lines of transgenic mice have been generated in the last 10 yr targeting different promoters e.

In these studies behavioral and neuropathological alterations were consistently observed in the lines expressing the highest level of the transgene or the severity of the mutation. In a subsequent study, marmoset monkeys were similarly injected with a different type of adeno-associated virus. The same symptoms appeared, but with a significant delay of almost 10—15 wk Eslamboli et al.

An attractive feature of this gene transfer model is that the use of adeno-associated viral vectors induces a progressive increase in protein expression that takes several weeks to reach its peak, with the lesion developing over a similar period of time. Overall, although none of the available transgenic models fully recapitulates the human disease, nevertheless they may represent an important tool for the study of new antiparkinsonian drugs directly targeting specific PD-related genes. Whereas PD has been originally described as a motor disease, the concomitant occurrence of nonmotor cognitive deficits is now widely recognized.

Consequently, the preclinical research is committed to develop new animal models to reproduce and investigate cognitive domains, such as attention, cognitive flexibility, planning, and problem solving, associated with an experimental parkinsonian condition. To this aim, the animal models described above are used to investigate the cognitive phenotype corresponding to an early, premotor stage of the disease.

We describe below some of the most common behavioral tests used to evaluate the cognitive performance of nonhuman primate and rodent animal models. The studies here reported and the results obtained are also summarized in Table 1. Summary of the original articles reviewed: Each study is reported indicating the animal model employed and the test used to assess the cognitive impairment. Most of the cognitive deficits revealed in MPTP-treated monkeys not only mimic those observed in PD patients but also resemble those found in patients with frontal lobe damage. Frontal lobes represent a complex integrative brain region that receives and sends projections to different areas and is involved in many cognitive and motor functions.

It has been suggested that the cognitive impairment found in PD patients could arise, at least in part, from the abnormal functioning of the prefrontal cortex basal ganglia—thalamocortical circuit, rather than from a localized frontal cortex dopamine deficiency Robbins and Arnsten ; Galvan and Smith In this context, the decisive role of the intralaminar thalamic nuclei in the transmission of salient sensory stimuli underlying attentional, rewarding, and reinforcing processes has been pointed out Matsumoto et al.

These nuclei represent the main source of thalamic inputs to the striatum and regulate the striatocortical pathway via the activation of striatal projection neurons and cholinergic interneurons. The object detour retrieval task ODRT is a behavioral test for monkeys that requires complex sequential motor planning and measures perseverative responses. The animal faces a transparent box with one open random side: The food present in the box can be grasped only if the box is entered from the correct side i.

The task reproduces a conflict between the visual information of the reward located in front of the subject with the tactile information indicating a barrier. To correctly perform the task, the monkey has to inhibit the impulsive response of direct horizontal movement of the arm toward the food, and actively search the open side of the box. It has been shown that MPTP-intoxicated monkeys are slower in performing this task as the post-MPTP period progresses, compared to controls, and normally show a higher number of wrong and perseverative responses barrier reaching , increasing in consequence the task completion time Schneider and Pope-Coleman Such a cognitive impairment is similar to that of monkeys with dorsolateral prefrontal cortex lesion, frontal lobe patients, and human infants younger than 1 yr old Diamond and Goldman-Rakic However, neither L-DOPA nor the selective agonist of the nicotinic acetylcholine receptor nAChR SIBY alone could ameliorate the cognitive aspect of the performance, although the former could at least improve the motor impairment induced by the neurotoxin Schneider et al.

Nonetheless, when combined together, the two treatments could bring significant improvements in both cognitive and motor functions, leading the authors to hypothesize that this drug combination may address the dopamine deficiency of PD while also addressing the reduction in noradrenergic and cholinergic function characteristic of the disorder Schneider et al. In the variable delayed response VDR task, the monkey is placed in front of two wells, one containing food and the other empty, that it can observe for 2 sec, before an opaque screen is lowered in front of the animal. The two wells are then covered with identical sliding plates, and the screen is removed.

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The ability of the animal to choose and uncover the well containing food is evaluated. The task is performed with variable delay lengths up to 60 sec. Control subjects perform the task with a delay-dependent increase in errors, up to a chance level, reflecting the limits of their short-term spatial memory. In contrast, MPTP-treated monkeys poorly perform in this test, shifting from a delay-dependent to a delay-independent performance profile, producing the same kind of errors as the control subjects, regardless of the delay length Schneider et al.

Coherent with this data, postmortem studies performed on MPTP-treated animals have shown that whereas cortical dopaminergic levels are intact, norepinephrine levels are reduced in both the cortex and the caudate nuclei. In this regard, it has been hypothesized that the rescue found following nAChR stimulation is mediated by the increase of norepinephrine release in these areas Schneider Moreover, also S, a dopamine D 3 receptor antagonist, could improve the percentage of correct response for the shortest delay Millan et al.

In order to better understand the cognitive nature of this deficit and to distinguish between the attentional and the working memory component involved in VDR tasks, a test variant with attentional cueing has been proposed. In this case, before the screen is lowered the examiner alerts the animal to the baiting of the well to ensure that the monkey pays attention to the wells. An additional variant of VDR is the modified delayed response MDR task, in which the attentional demands of the task are manipulated to allow good performance in trials with low attentional load and impaired performance in trials with higher attentional load by increasing the length of time of cue presentation.

Also in this case, the presence of the cue, as well as its duration, could improve the performance. Notably, L-DOPA administration, in a dosage that maximally improved parkinsonian motor symptoms, had a detrimental effect on the task performance, while SIBA had, once again, a beneficial effect on it Decamp and Schneider , Schneider et al. Those studies demonstrated that the impaired performance in VDR task is mainly due to an attentional rather than a working memory deficit in this model.

The attentional set-shifting test ASST evaluates cognitive flexibility and set-shifting ability in monkeys. To perform this task, the animal is required to perform different subtests in which it must develop and maintain an appropriate response strategy across changing stimulus characteristics by shifting the attention focus among different aspects of the same object and adjust the behavioral response according to subtest rules.

MPTP-intoxicated monkeys were still able to perform all stages of the task with a normal overall response latency. However, with the exception of the simple discrimination, their performance was significantly impaired in all other subtests, with particular difficulty in the discrimination reversal and extra-dimensional shift EDS subtests, where they produced a bigger number of errors i. S, in this case, could ameliorate the primate performance in EDS Millan et al. The use of PD rodent models obtained through the brain injection of 6-OHDA or MPTP represents a manageable, reproducible, and valid tool for the study of cognitive symptoms such as executive dysfunction, memory impairment, and visuospatial deficits for a more extensive review on NMS in rodents, refer to Lindgren and Dunnett The Morris water maze MWM is an extensively used behavioral test for the study of visuospatial memory in rodents.

Indeed, in the early stages of PD, patients tend to show spatial memory impairment with a relative preservation of perceptive visuospatial and executive functions mainly due to striatal involvement Pillon et al. However, as the disease progresses, multiple and severe spatial memory impairments appear Owen et al. Thus, different versions of MWM seem to be ideal to model these types of deficit observed in patients. Regardless of the version used, the MWM apparatus consists of a pool filled with opaque water and containing a platform. This protocol requires a short training phase.

In the test phase, the latency to reach the platform is measured.

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In the test phase, the platform is removed and the time spent by the animal in the area where the platform was is used as a measure of spatial learning; this version of MWM requires that the animal build a spatial representation that guides it toward the platform. The latency to reach the platform during the training session is usually adopted as a measure of the learning process, while the test performance is an index of the solidity of the acquired memory. The performance in the former protocol is mainly mediated by basal nuclei, while in the latter it is largely dependent on the hippocampus McDonald and White The selective involvement of these different brain structures in the two versions of the MWM is clear from the results of several studies.

A selective lesion in the SNpc Miyoshi et al. Those behavioral observations were accompanied by a reduction of dopamine levels in the striatum and prefrontal cortex, but not in the hippocampus Miyoshi et al. Moreover, in the aforementioned study conducted by Da Cunha and colleagues, the otherwise normal performance in the spatial version of the test could be worsened by hippocampal injection of lidocaine Da Cunha et al.

Indeed, MFB includes projections from both SNpc and the ventral tegmental area; the latter is the origin of the meso—cortico—limbic dopaminergic pathway that projects also to the CA1. Moreover, Costa et al. Novel object rRecognition NOR and spatial object recognition SOR are two memory tests frequently used to investigate attention, discrimination, and spatial memory in rodents.

Both these tests measure the ability of the animal to detect a change in the object physical characteristics or in its spatial location, and rely on the natural attraction of rodents for the novelty. After a variable delay, the animal is required to remember the familiar object and discriminate it, during the test, from a new object NOR , or detect the shifted position of a familiar object to a new location SOR. Postmortem analysis revealed both hippocampal microglial activation and decreased density of pyramidal neurons in the CA1 area Sy et al.

These data are in agreement with microglial activation and increased levels of inflammatory cytokines observed in the SNpc, putamen, and hippocampus of PD patients Sawada et al. In a similar model, chronic administration of MK, a noncompetitive NMDA receptor antagonist, resulted in a mild improvement of the performance, accompanied by a partial recovery of dopaminergic transmission in SNpc and striatum Hsieh et al. The authors suggest that the MPTP injection induces an excitotoxic release of glutamate in the striatum and a consequent neuroinflammatory response in the hippocampus, which is rich in NMDA receptors and mediates memory functions Hsieh et al.

On the other hand, bilateral injections of 6-OHDA in the mouse striatum selectively impaired the performance in the long-term, but not in the short-term NOR test Bonito-Oliva et al. In this study, the authors attributed the memory impairment to a deficient long-term potentiation in the dentate gyrus, but not the CA1 area of the hippocampus.

In fact, both the memory deficit and long-term plasticity were reverted by the administration of L-DOPA or the selective dopamine D1 receptor agonist SKF, but not the D2 receptor agonist pramipexole Bonito-Oliva et al.

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In another study, it has been shown that systemic administration of MPTP in mice produces a gradual impairment in the short-term NOR that correlates with the progressive impairment of long-term potentiation in the CA1 area of the hippocampus Moriguchi et al. On the other hand, when tested for their spatial memory, mice injected with 6-OHDA in the striatum were impaired in both the short- and the long-term SOR, suggesting a predominant role of dopamine in modulating acquisition and maintenance of spatial information De Leonibus et al.

The same authors successively showed that this deficit is restored by the administration of the mGluR5 selective antagonist MPEP, suggesting the possibility of a presynaptic modulatory action of mGluR5 receptors on the dopamine release from the residual nerve terminals De Leonibus et al.

T-Maze and Y-Maze are two classic behavioral tests to measure reference and working memory in rodents. Despite the simple structure of the apparatus Y or T shapes , different paradigms can be applied to study discrimination, and spontaneous and controlled alternation between the arms of the maze. Placed in the center, rodents explore the apparatus with the tendency to enter the arm visited less recently.

An alternative protocol is based on the controlled alternation between arm entries, achieved by rewarding one arm with the presence of food. The animal is trained to discriminate and memorize the goal rewarded arm that can be fixed or can alternatively change according to a criterion.

Rats bilaterally injected in the SNpc with MPTP were able to perform the task when the reinforced arm was always the same, but were unable to learn the criterion in the alternate choice protocol Braga et al. Similar findings are reported in MPTP-intoxicated mice impaired in the ability to acquire the criterion dependent on the duration of the delay between training and test Tanila et al. Active avoidance AA is a memory task based on associative and emotional learning. In AA, the animals are trained to associate the presentation of a specific cue with the subsequent occurrence of a negative event shock and to actively prevent the shock by moving to a different place in the apparatus.

The learning is inferred by the number of correct responses to the cue presentation escape and shock avoidance and the response latency. These data are in line with the presence of Lewy bodies and Lewy neurite deposits in the amygdala of PD patients Braak et al. The operant task conditioning OTC is a well-established behavioral task used to test cognitive impairment in several rodent models.

Generally, the animal is trained to learn an operant behavior, aimed at receiving a reward or avoid a punishment. In the lateralized nose-poke task, the animal faces a wall with three holes surmounted by three lights: A sustained nose-poke in the central hole triggers one of the lateral lights and food reward is provided from the hole ipsilateral same version to the light or, in a more complex protocol, opposite opposite version to it.

In a similar test, Thy1-aSyn transgenic mice showed an impairment in the reversal phase of the task Magen et al. The operant task protocol can be manipulated in order to test the animal attention and motor response preparation. This is done by training rats with a bilateral striatal 6-OHDA lesion to press a lever and wait until a luminous cue guides them to the hole with food reward; when the interval was rendered unpredictable by random duration the lesioned animals were significantly impaired Baunez and Robbins In a similar paradigm the lever had to be kept pressed until a light cue of a random duration was turned off in order to retrieve the food, the reaction time performance of lesioned rats was compromised by premature or delayed lever release Turle-Lorenzo et al.

Chronic treatment with L-DOPA or the dopaminergic D2-like receptor agonist piribedil allowed a rapid and full recovery. The aim of this short review was to offer an overview on the state of the art of the research on the cognitive deficits associated with PD, as addressed by behavioral studies in rodents and nonhuman primates. In the last few decades, the occurrence of nonmotor, cognitive symptoms in PD patients became an increasingly recognized issue. As a consequence, the preclinical research has generated a number of new animal models for the study of different aspects of the cognitive impairment associated with the disease.

Despite the limits of each of these models, it has been possible to precisely mimic several of the most important cognitive symptoms occurring in PD patients, such as impairment in executive functions in forms of novel, spatial, and discriminative memory, attention, and problem solving. Regardless of some discrepancies in the data obtained, probably due to the differences in the protocol adopted and in the animal strain employed, these animal models have been able to reproduce the cognitive deterioration observed in both early and late parkinsonian conditions.

Moreover, these animal models also showed biochemical and electrophysiological dysfunctions in the same anatomical sites found in patients, such as the prefrontal cortex and the hippocampus. Since our understanding of the molecular and cellular mechanisms underlying the progressive loss of the executive functions in PD is still quite fragmented, the availability of faithful animal models will certainly allow a rapid comprehension of the neurobiological processes underlying cognitive NMS. Moreover, a clear pathophysiological characterization of the link between motor symptoms and cognitive deficits in PD will be a necessary step toward future therapies able to globally manage all aspects of the disease, a goal eventually to be achieved in the years to come.

This work was supported by the Michael J. Email brambilla. Previous Section Next Section. View this table: In this window In a new window. Table 1. MPTP-based nonhuman primate model Most of the cognitive deficits revealed in MPTP-treated monkeys not only mimic those observed in PD patients but also resemble those found in patients with frontal lobe damage.